Estudi dels desequilibris cromosòmics en tumors sòlids epitelials esporàdics i familiars

Abstract

Under the concept of cancer there is a group of more than a hundred illness that are caracterized by the accumulation of multiple genetic alterations. We have focused our study in three different kinds of epithelial solid tumours: sporadic bladder tumours, hereditary or familial colorectal cancer and kidney cancer. In order to analyze these tumours, we applied the Comparative Genomic Hybridization (CGH) technique. The global analysis of the tumoral genome allowed by this technique provides information about the frequency of unbalances, the regions where these unbalances are located and about which of these regions could be more susceptible to contain tumour supressor genes or oncogenes. Moreover, this technique also allows us to perform clonality studies and to detect different patterns of chromosomal evolution. In the bladder tumours, we observed that the genomic damage increases with the tumoral stage and grade. The unbalances that were more frequently found were the losses of 9q, 9p, 5q, 8p and the gains of 1q, Xq, 17q, 8q and 20q. However, there is a group of abnormalities that present significant differences among the different tumoral stages. Between pTa and pT1, are the losses of 5q, 9p, 9q, 10q, 8p, 11q, 18q and the gains of 8q and 10p. Between pT1 and pT2-4, are the gains of 5p, 7p, 3p, 10p and the loss of 6q. The classification of the superficial or minimally invasive tumours according to their observed patterns of genomic unbalances allowed us to subclassify them in three different subgroups. The first subgroup was characterized for the predominance in gains, being +1q, +1p, +17q and +19p the most frequents. The second subgroup was characterized for the losses of 9q, 9p, 11q, 8p, 5q, 11p and the third subgroup was characterized for a low number of unbalances. The fact of finding two subgroups with complex karyotypes could suggest that these tumours could have evolved from two different pathways, one characterized for gains and the other for losses. On the other hand, 30% of the bladder tumours present multiplex damages, and this fact makes these tumours an excellent model for the analysis of the different relations between sincronous sporadic tumours. The study of sincronic tumours from the same patient confirmed their monoclonal origin and allowed us to design the evolutive pathway from a single original tumour. We performed two analysis, one in tumours of patients affected of Hereditary Papilary Renal Cancer (HPRC) and one in tumours of patiens affected of Familiar Adenomatose Poliposi (FAP). These kind of tumours provides an excellent natural model to study the chromosomal aberrations in primary stages of tumoral evolution. In addition, they provide important information about the dynamics of formation of these aberrations in the tumours. Identic structural chromosomal aberrations were found in different tumours of the same patient affected of HPRC. This fact suggest either a common embrionary origin or conditioned adquisition of alterations in specific chromosomal regions due to the genetic predisposition. The behaviour of the MET gen was also studied in these patients. The duplication of the MET gen was found to be associated with the trisomy of chromsome 7. In those tumours with tetrasomy of chromosome 7, both normal and mutated alleles were found to be duplicated. The analysis of unbalances present in adenomes and carcinomes from patients affected of FAP allowed the establishment of evolution patterns of colorectal cancers. We observed that the different adenomes from a same patient affected of FAP display a strong genetic relation, which indicates a common evolution pattern. Again, this fact suggest that the genetic predispostion may direct the adquisition of genomic alterations in specific chromosomal subregions.

Date of Award	21 Dec 2005
Original language	Undefined/Unknown
Supervisor	Antoni Gelabert Mas (Director) & Rosa Miró Ametller (Director)